Rodent sterilant process and bait

ABSTRACT

PHARMACEUTICAL PREPARATIONS IN DOSAGE FORMS AND ANIMAL FEEDS (BAITS) CONSISTING ESSENTIALLY OF PHARMACEUTICALLY ACCEPTABLE CARRIERS, ORAL AND INJECTABLE, COMPOUNDED WITH A SUB-LETHAL, YET EFFECTIVE, AMOUNT OF A COMPOUND HAVING THE FORMULA:   CL-CH2-CH(-O-R)-CH2-O-CH2-CH(-O-R1)-CH2-CL   WHEREIN R AND R1 CAN BE HYDROGEN OR AN ACYL RADICAL OF A HYDROCARBON CARBOXYLIC ACID OF 1 TO 18 CARBON ATOMS, INCLUSIVE FOR INDUCING STERILITY IN MALE MAMMULS. METHODS FOR PREVENTING IMPREGNATION OF FEMALES BY MALE MAMMALS WHICH COMPRISES ADMINISTERING SYSTEMICALLY TO MALE MAMMALS A STERILIZING AMOUNT OF A COMPOUND OF THE FORMULA.

United States Patent O 3,659,021 RODENT STERILANT PROCESS AND BAIT Gilbert A. Youngdale, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed May 5, 1970, Ser. No. 34,857 Int. Cl. A01n 9/24; A61k 27/00 US. Cl. 424342 6 Claims ABSTRACT OF THE DISCLOSURE mammals a sterilizing amount of a compound of the formula.

BRIEF SUMMARY OF THE INVENTION This invention relates to pharmaceutical preparations and methods of use thereof. The pharmaceutical preparations are compounded with edible and injectable carriers to prepare baits, capsules, both hard and soft, suspensions, and injectables. The preparations contain an effective amount of a compound of the Formula 1 for bringing about steriity in the male mammals, for example, monkeys, rats, hamsters and guinea pigs.

DETAILED DESCRIPTION Compounds of the formula can be prepared by methods disclosed in French Pat. 1,055,569, C.A., 53, 1154 (1959).

The pharmaceutical preparations are compounded along with suitable oral and injectable carriers to prepare the aforesaid dosage forms. The capsules for oral use are hard gelatin capsules or soft gelatin capsules, containing the active ingredient alone or admixed with an edible oily medium, for example, cottonseed oil, peanut oil, and mineral oil. Elixirs and syrups are formulated with suitable sweetening agents, for example saccharin, cyclamate and sucrose, and diluents such as ethanol, glycerol andsorbitol. They may contain a demulcent and are preferably flavored and colored to provide orally acceptable preparations. Advantageously they contain a suitable preservative such as methylor propylparaben. Emulsions suitable for oral use are of both the oil/ water and water/oil types. Also, the essential active ingredient may be in the form of a water-insoluble liquid which is dispersed in the emulsion bases. The emulsions contain emulsifying agents such as acacia and tragacanth and surfactants, for example, polysorbate '80 and poloxakol. Solutions of the watersoluble compounds are prepared by simple admixture with water which advantageously contains a preservative such as methylor propylparaben. Oil dispersions contain the essential active ingredient and may include a demulcent, for example carboxymethylcellulose, alginate, polyvinylpyrrolidone, along with a dispersing agent such as lecithin. The dispersions also contain suitable preservatives, for example, propylbaraben. Dosage forms for injectable use are sterile solutions, the pure compound in sterile form, and sterile emulsions. Such preparations for injectable use must be sterile and must contain bacteriostatic preservative agents according to the art.

3,659,021 Patented Apr. 25, 1972 Oral dosage forms, as heretofore described, contain from about 0.025 to about 3.0 gm. of the essential active ingredient per unit dose, but are not limited thereto, since Within such range they include, for example, 0.05 gm., 1.0 gm., and 2.5 gm. Sterile liquid forms for injectable administration contain from about 25% to 50% of the essential active ingredient but are not limited thereto, since they include within this range, for example 30%, 35%, and 40%. Liquid oral dosage forms contain from about 5% to 50% of the essential active ingredient but are not limited thereto, since within this range are included, for example 10%, 15%, 25 and 40%. These dosage forms provide, generally, a dosage range of essential active ingredient from about 0.25 to about 5.0 gm. per day. The daily oral and parenteral doses are approximately the same except for sustained parenteral dosage forms which contain from about 0.25 gm. to about 1.0 gm. of essential active ingredient per ml. and are given once a month intramuscularly. The usual oral and parenteral forms are to be administered once per day. Other ingredients, which are however not essential to the present invention, are, for example, a progestational agent such as medroxyprogesterone or melengestrol acetate, given in the usual dosage regime 'for such active ingredient.

Mature virgin male rats are checked for ability to mate by placement with immature female rats primed with gonadotropic factor of pregnant mares serum. Those males which mate are used for subcutaneous injection or oral administration of the novel pharmaceutical preparations. The essential active ingredient is prepared as a 60.0 mg./ml. dispersion in 0.25% aqueous methylcellulose in sterile vehicle. This pharmaceutical composition is admimstered to each of three mature mating males, a half ml. per day subcutaneously or orally for eight days. These treated males are exposed to receptive mature females for mating and mating is checked by the presence of sperm with or without a plug in the vagina of the female. Approximately ten days thereafter, the females are examined for the presence and number of implantation sites, and the ability of the pharmaceuticalcompositions to prevent rmpregnation by the mature male is shown by the absence of implantation sites at autopsy.

The following examples illustrate the manner and process of making and using the invention but are not to be construed as limiting.

EXAMPLE 1 EXAMPLE 2 The mono and di-benzoate ester of 1,l'-oxybis[3-chloro- 2-propanol] in the form of a pharmaceutical preparation, provided an oral pharmaceutical preparation effective in preventing implanation.

EXAMPLE 3 The mono and di-acttate ester of 1,1'oxybis[3-chloro- Z-propanol] were likewise tested according to procedures given heretofore and found capable of preventing impregnation by the male.

EXAMPLE 4 An oral pharmaceutical preparation containing 1% of 1,1 oxybis[3-chloro-2-propanol] in 0.25% aqueous methylcellulose was administered orally to mating mature EXAMPLES:

A sterile aqueous solution for injectable use is prepared.

to contain 300 mg./ml. of 1,1 oxybis[3-chloro-2 -propanol]. The injection of 1 ml., per day is effective to preventimpregnation of receptive female monkeys-by a mature male. v v

Additional embodiments of the presentinventive concept'are baits, i.e., rations, for oral ingestion by rodents, especially rats, and methods of controlling rodent population, especially active ingredient and, in amounts that are attractive to' the animals in the sense that they are not repelled thereby, edible dietary constituents such as protein, fat, carbohydrate, minerals and vitamins.

The medicated ration must not repel the rodents although it does not necessarily have to attract in the sense of being absolutely preferred over other rations. Hence, the medicated ration retains the natural flavor of the dietary constituents after the essential active ingredient is incorporated therein. Such incorporation provides a final mixture or blend throughout which the active ingredient is uniformly distributed. Such active ingredient can be added to the ration by mixing both as solids or as liquids, by addition to 'a solid ration of a solution or suspension in water or ethanol; by adding the active ingredient in a liquid which-is then removed to leave adry solid mixture, for example, a solution or suspension in water or ethanol; by adding the active ingredient in the form of coated particles or pellets, coated, for example, by coacervation with gelatin, or by coating with an alcohol solution of a .Water-'soluble type of ethyl cellulose. The final ration c'ontainingthe coated particles or pellets is the preferred form because of its tendency to better mask any undesirable taste of the essential active ingredient. The rations contain the essential active ingredient in a concentration suflicient to cause lesions in the excur-rent duct (epididymal lesions) and permanent infertility in. other wise fertile male animals, especially rats, when they ingest the compositions in-their usual manner of providing for their metabolic needs. Illustratively, most mature male rats that ingest an amount of the ration providing at least about 100 mg. per kilogram of rat body weight become irreversibly infertile as shown by epididymal lesions and by sterile mating with fertile females. As will be apparent, rats eating ad libitum will consume different amounts of the active ingredient-containing rations. Hence, to provide about 100 mg. per kilogram in a rat eating a smaller amount of the effective ration, a more concentrated ration must be provided than for a rat consuming a larger amount of the same ration. In the latter case, a less conoentrated ration is operable. For example, in rats weighing about 200 to 250 gm. and consuming about to 25 gm. of ration at one feeding, the ration may contain 0.25% by weight of the active ingredient. Thereby, the 250 gm. rat consuming 10 gm. of the treated edible preparation ingests 25 mg. of the active ingredient equivalent to about 100 mg. per kilo. With this same ration containing 0.25% active ingredient, a 200 gm. rat eating 25 gm. at one feeding ingests 62.5 mg. of the active ingrediennequivalent to about 312.5 mg. per kilo. Such variations will occur due to the eating habits of the rats.- Hence, various embodiments of the rodent-control preparations are within the inventive concept provided they contain an effective amount of the essential active ingredient to cause the males to acquire the epididymal lesions of infertility. y n

J i The aforesaid embodi cuts of this inventive co ncept ingredient amounts to from about 0.05% to about 0.5%,

such range being not limited thereto for it includes within the range the other percentages such as 0.1%, 0.2%, 0.3%, and0.4%.- A more concentrated.preparation, say up to about 1.0% or even 5.0, is satisfactory provided it is, upon use, diluted with the'aforesaid'edible dietary constituents to provide operative amounts of the essential active ingredient without wasting active material. These embodiments of the inventive concept are made available to the animals, especially rats, for control of the population thereof by placing the preparation in and about the locales available to and frequented by the rodents.

I claim: v I

1. A pharmaceuticalpreparation for preventing impregnation of receptive sexually mature female rodents by the male counterparts thereof in the form of an oral ration for rodents consisting essentially of an effective amount for producing epididymal lesions and infertility in male rodents of a compound of the formula wherein R and R can-be hydrogen or an acyl radical of a hydrocarbon carboxyl'ic acidof 1 to'l8 carbon atoms, inclusive, compounded with an ingestible bulking agent acceptable to said rodents, said ration providing at least about 100 rug/kg. of male rodent body weight.

2. The ration of claim 1 wherein the compound is 1,1- oxybisE 3-chloro-2-propanol] 3. The ration of claiinl which-contains from about 0.05% to about 0.5% by weight of said compound.

4. A method of producing 'epididymal lesions and infertility in male rodents which comprises supplying to said rodents in locales available to and frequented by said rodents a ration supplying an effective amount for producing the lesions and infertility of a compound of the formula pa on oncmorPomoombnoHm wherein R and R 'are hydrogen or an acyl radical of a hydrocarbon carboxylicacid of 1 to 18 carbon atoms,

inclusive. 1 v v S. A method of claim 4 wherein the effective amount is at least about 100 trig/kg. of body weight ofsaid male rodents.

6. The method of. claim 4 wherein the compound is l,1-oxybis [3 -chloro -2-propanol] 

